Tumor progression is thought to occur when variant cells having selective growth properties arise within a tumor cell population (Foulds (1975) Neoplastic Dev., Vol. 2, Academic Press, London). One of the final stages of tumor progression is the appearance of the metastatic phenotype (Nicolson (1984) Cancer Metast. Rev. 3:24-42). During metastasis, the tumor cells invade the blood vessels, survive against circulating host immune defenses, and then extravasate, implant, and grow at sites distant from the primary tumor (Nicolson (1982) Biochim. Biophys. Acta 695:113-176; and Nicolson (1987) Cancer Res. 47:1473-1487). This ability of tumor cells to invade neighboring tissues and to colonize other organs is among the leading causes of cancer-related deaths.
The term metastasis encompasses a number of phenotypic traits which together result in the clinical problem that most often leads to death from cancer. The cells lose their adherence and restrained position within an organized tissue, move into adjacent sites, develop the capacity both to invade and to egress from blood vessels, and become capable of proliferating in unnatural locations or environments. These changes in growth patterns are accompanied by an accumulation of biochemical alterations which have the capacity to promote the metastatic process.
Metastatic cancer may invade many different regions of the body, bone being one of the most frequent sites. For example, the metastases from carcinomas and occasionally even from sarcomas are known to spread to the skeleton. Skeletal metastases may be silent or produce symptoms by the same mechanisms as primary tumors, i.e., pain, swelling, deformity, encroachment on hematopoietic tissue in the bone marrow, compression of spinal cord or nerve roots, and pathologic fractures. In addition, rapidly lytic skeletal metastases can result in hypercalcemia. Because of the painful and often debilitating effects of such metastases, better treatment and improved regimens are urgently needed.
So far, little is known about the intrinsic mechanism involved in the metastatic cascade. It is likely that in some cases the augmented metastatic potential of certain tumor cells may be due to an increased expression of oncogenes, which normally are responsible for control of various cellular functions, including differentiation, proliferation, cell motility, and communication (Cairns (1981) Nature 289:353-57; Berger et al. (1988) Cancer Res. 48:1238-1243; and Klein et al. (1985) Nature 315:190-195).
In recent years, several genes postulated to be involved in this process have been identified. For example, some members of the S100 family of Ca.sup.2+ -binding proteins may have relevance to different aspects of neoplastic progression, tumorigenicity, and metastatic potential (Ebralidze et al. (1989) Genes & Dev. 3:1086-1092; Lee et al. (1992) Proc. Natl. Acad. Sci. 89:2504-2508)). This family consists of 13 human members expressed in a tissue- and cell-specific manner. These proteins have been found in various human tumors such as virtually all primary and metastatic melanomas, and have been used as a marker for the identification of tumor histopathogenesis (see, e.g., Lee et al. (1992) Proc. Natl. Acad. Sci. (USA) 89:2504-2508). The normal cellular functions of the S100-proteins have not been clarified, although several have been suggested, including involvement in essential signal transduction pathways, regulation of cell growth and differentiation, and participation in cytoskeletal organization (Kligman et al. (1988) Trends. Biol. Sci. 13:437-443).
One particular human S100 protein has been found to be encoded by the CAPL gene localized to chromosome 1 (Iq2-22) together with at least five other structurally related genes. (Englekamp et al. (1992) Biochem. 31:10258-10264; Engelkamp et al. (1993) Proc. Natl. Acad. Sci. (USA) 90:6547-6551). Its murine counterpart, mts1 is expressed in metastatic murine mammary carcinoma (Ebralidz et al. (1989) Genes Dev. 3:1086-1093). These genes, encoding small (10 kD) Ca.sup.2+ -binding proteins of the S100-family, share a high degree of homology, particularly in regions that encode the Ca.sup.2+ -binding domains (Moncrief (1990) J. Mol. Evol. 30:522-562.
The mechanism by which cancer becomes metastatic, as well as the function of the S100-related genes and proteins in the progression of metastatic cancer has yet to be elucidated. A better understanding of these underlying processes will provide more effective methods of treating and controlling metastatic cancer which are surely needed, including methods of inhibiting the expression of genes involved in the progression of the disease.